The m6A reader IGF2BP2 regulates glutamine metabolism and represents a therapeutic target in acute myeloid leukemia.

N 6-Methyladenosine (m6A) modification and its modulators play critical roles and show promise as therapeutic targets in human cancers, including acute myeloid leukemia (AML). IGF2BP2 was recently reported as an m6A binding protein that enhances mRNA stability and translation. However, its function in AML remains largely elusive. Here we report the oncogenic role and the therapeutic targeting of IGF2BP2 in AML. High expression of IGF2BP2 is observed in AML and associates with unfavorable prognosis. IGF2BP2 promotes AML development and self-renewal of leukemia stem/initiation cells by regulating expression of critical targets (e.g., MYC , GPT2 , and SLC1A5) in the glutamine metabolism pathways in an m6A-dependent manner. Inhibiting IGF2BP2 with our recently identified small-molecule compound (CWI1-2) shows promising anti-leukemia effects in vitro and in vivo. Collectively, our results reveal a role of IGF2BP2 and m6A modification in amino acid metabolism and highlight the potential of targeting IGF2BP2 as a promising therapeutic strategy in AML. [Display omitted] • IGF2BP2 is overexpressed in AML (especially LSCs) and associated with poor outcome • IGF2BP2 promotes AML initiation/development and maintenance as an m6A reader • IGF2BP2 controls glutamine metabolism in AML by targeting GPT2 , SLC1A5 , and MYC • Pharmacological inhibition of IGF2BP2 represents a new strategy for AML therapy Weng et al. report that IGF2BP2 is highly expressed in leukemia stem cells and promotes development/maintenance of acute myeloid leukemia (AML) by regulating glutamine metabolism as an m6A reader. Targeting IGF2BP2 by the newly developed compound CWI1-2 represents a promising therapeutic strategy for AML therapy. [ABSTRACT FROM AUTHOR]